1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to aryl substituted pyrazoles, imidazoles, oxazoles thiazoles and pyrroles, and the discovery that these compounds are anticonvulsants and act as blockers of sodium (Na+) channels.
2. Related Background Art
Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na+ channel activity (Catterall, W. A., Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Naxe2x88x92 ions.
Recently, other Na+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).
The neuroprotective activity of Na+ channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Naxe2x88x92 channel blockers prevent hypoxic damage to mammalian white matter (Stys el al., J. Neurosci. 12:430-439 (1992)). Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.
Another example of clinical use of a Naxe2x88x92 channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensim et al., New Engl. J. Med. 330:585-591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76 (1994)). Furthermore, based on a number of similarities between chronic pain and tinnitus (Moller, A. R. Am. J. Otol. 18: 577-585 (1997); Tonndorf, J. Hear. Res. 28: 271-275 (1987)) it has been proposed that tinnitus should be viewed as a form of chronic pain sensation (Simpson, J. J. and Davies, E. W. Tip. 20: 12-18 (1999)). Indeed, lignocaine and carbamazepine have been shown to be efficacious in treating tinnitus (Majumdar, B. et al. Clin. Otolaryngol. 8: 175-180 (1983); Donaldson, I. Laryngol. Otol. 95: 947-951 (1981)).
It has been established that there are at least five to six sites on the voltage-sensitive Na+ channels which bind neurotoxins specifically (Catterall, W. A., Science 242:50-61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na+ channels, exert their action by interacting with the intracellular side of the Na+ channel and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)). 
PCT International Published Application WO96/40628 discloses semicarbazones represented by the following Formula:
where R1-R4 are independently hydrogen, halogen, C1-9 alkyl, C3-9 cycloalkyl, cyano, C1-9 alkoxy, or C6-10 aryloxy; R5 is hydrogen, C1-9 alkyl, C3-9 cycloalkyl, or C6-10 aryl; and X is oxygen or sulfur. The compounds are disclosed to be useful as anticonvulsants.
Dimmock et al., (J. Med. Chem. 39:3984-3997 (1996)) discloses (aryloxy)aryl semicarbazones that displayed anticonvulsant activities when administered intraperitoneally to mice or orally to rats.
Pevarello et al., (J. Med. Chem. 41:579-590 (1998)) discloses 2-[(arylalkyl)amino]alkanamide derivatives represented by the following Formula: 
where R1 is chloro, fluoro, trifluoromethyl, R2 is chloro, cyano, fluoro, methyl, nitro, methoxy and trifluoromethyl, R3 is chloro and fluoro and X is CH2O, a bond, CH2, CH2CH2, CH2S, CH2NH, OCH2, CH2CH2O, CH2CH2CH2O, CH2N(Me), NHCH2, CONH and CHxe2x95x90CH. The compounds are disclosed to be useful as anticonvulsants due to activity as sodium channel blockers.
PCT International Published Application WO 98/52940 discloses substituted pyrazoles of the following Formulae: 
where R1 is alkylsulfinyl, arylsulfinyl, alkylsulfonyl and acyl and R3 is limited to pyridinyl, pyrimidinyl, quinolinyl, purinyl, C-attached malemides and pyridiones. The compounds are disclosed to be useful as p38 kinase inhibitors.
PCT International Published Application WO 98/50348 discloses substituted sulfonamides of the following Formula: 
where Z is a heteroaryl group. The compounds are disclosed to be metalloproteinase inhibitors.
Japanese Patent Application JP 10168063 (CA 129:91737) discloses compounds of the following Formulae: 
The compounds are described as microbiocides.
European Patent Application EP 446180 discloses substituted pyrazoles of the following Formula: 
wherein X is oxygen and Y is OC2H5 or OH. The compounds are disclosed as starting materials.
Radwan, S. M. (Collect. Czech. Chem. Commun. 57(7). 1553-1558 (1992)) describes the synthesis of the compound of the following Formula: 
Korshak, K. K., et al., (Polym. Sci. USSR (Engl. Transl.) 6: 1087, 1196-1198 (1964) and J. Polym. Sci. Part A 3: 2425-2439 (1965)) describe the synthesis of the following compounds: 
Stille et al. (J. Polym. Sci. Part A-1 6: 2317-2330 (1968)) describe the synthesis of the following compound: 
Szmant et al., (J. Am. Chem. Soc. 78: 4386-4389 (1956)) describes the following compound : 
Grandberg et al. (J. Gen. Chem. USSR (Engl. Transl) 30: 1404-1408 (1960)) describe the synthesis of 3-(4-phenoxyphenyl)pyrazoles of the following Formula: 
where R1 is hydrogen or C(O)NH2. With R1 hydrogen, the picrate salt was also prepared.
The following pyrazoles are part of the available chemical directory (ACD):
2-chloro-6-[4-(1H-pyrazol-5-yl)phenoxy]benzonitrile; 2-chloro-6-[4-(1-methyl-1H-pyrazol-5-yl)phenoxy]benzonitrile; 2-chloro-6-[4-[1-(4-chlorobenzoyl)-1H-pyrazol-5-yl]phenoxy]benzonitrile; 2-[4-(1-acetyl-1H-pyrazol-5-yl)phenoxy]-6-chlorobenzonitrile; 2-chloro-6-(-4-[1-[(4-chlorophenyl)sulfonyl]-1H-pyrazol-5-yl]phenoxy)benzonitrile; 2-chloro-6-[4-[1-(methylsulfonyl)-1H-pyrazol-5-yl]phenoxy]benzonitrile; 2-chloro-6-[4-[1-(4-chlorophenyl)-1H-pyrazol-3-yl]phenoxy]benzonitrile; 3-(4-phenoxyphenyl)-1H-pyrazole; 3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole; 3-[4-(4-methoxyphenoxy)phenyl]-1H-pyrazole; 3-[4-(phenylthio)phenyl]-1H-pyrazole; 3-[4-(phenylsulfonyl)phenyl]-1H-pyrazole; 5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazole; N1-phenyl-5-(methylthio)-3-(-4-phenoxyphenyl)-1H-pyrazole-1-carboxamide; (4-chlorophenyl)[5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl]methanone; N1-(4-chlorophenyl)-5-(methylthio)-3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide; [5-(methylthio)-3-(-4-phenoxyphenyl)-1-pyrazol-1-yl](phenyl)methanone; 3-(2-chloro-4[4-chlorophenoxy])phenyl pyrazole; 1-phenylcarbamoyl-3-(2-chloro-4-[4-chlorophenoxy]phenyl pyrazole; 3-(2-chloro-4[4-chlorophenoxy])phenyl-1-(4-chlorophenylcarbamoyl)pyrazole; 3-(2-chloro-4[4-chlorophenoxyl]phenyl-1-(4-chlorobenzoyl)pyrazole; 1-(4-chlorobenzenesulfonyl-3-(2-chloro-4-[4-chlorophenoxy]phenylpyrazole; 1-(2,4-dichlorophenylsulfonyl)-3-dimethylamino-4-(4-phenoxyphenyl)-pyrazole; N1-phenyl-5-morpholino-3-(4-phenoxypheny)-1H-pyrazole-1-carboxamide; 3-chloro-2-[5-[4-(phenylthio)phenyl]-1H-pyrazol-1-y]-5-(trifluoromethyl)-pyridine and 2-chloro-6-[4-(1-methyl-1H-pyrazol-3-yl)phenoxy]-benzonitrile.
Yamada et al. describe in Biosci. Biotechnol. Biochem. 56:1943-1948 (1992) the synthesis of the compounds of the following formula: 
wherein R is H or Et. The compounds were inactive as bleaching agents in lettuce seedlings.
Kuwano et al. (Agric. Biol. Chem. 55:2999-3004 (1991)) describe the synthesis of the compound of the formula: 
The compound is described as an insecticide.
Walker et al. (J. Chem. Soc. 347-350 (1942) describe the following compound as its picrate salt: 
Schubert et al. (J. Prakt. Chem. 18 (No. 3-4): 192-202 (1962)) describes a compound of formula: 
European Patent Application No. 269238 describes 2-(4-phenoxyphenyl)-14-imidazole-4,5-dicarbonitrile and 5-cyano-2-(4-phenoxyphenyl)-1H-imidazole-4-carboxamide as plant growth regulators.
WO 99/11627, JP 05287563, JP 59075257, Todorova et al. (Tr. Nauchnoizsled. Khim.xe2x80x94Farm. Inst. 10: 85-94 (1978)), and Vodenicharov et al. (Dokl. Bolg. Akad. Nauk 31(4): 441-444 (1978)) describe substituted benzimidazole derivatives.
Golanova et al. (Zh. Org. Khim. 29:1319-1324 (1993)), Ermikow et al. (Z. Obshch. Khim. 58: 450-457 (1988)), and Trofimov et al. (Khim. Geterotsikl. Soedin. 4: 489-491 (1978)) disclose 2-(4-phenoxyphenyl)-1H-pyrrole. No pharmaceutical use is described or suggested.
JP 07025849 describes a method for preparing 5-(4-phenoxyphenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carbonitrile which is stated to be useful as intermediate for agrochemicals and pharmaceuticals.
Korostova et al. (Khim. Geterotsikl. Soedin. 5: 609-613 (1992)) disclose the synthesis of 2-[4-(phenylthio)phenyl]-1H-pyrrole.
Anderson et al. (J. Med Chem. 22: 977-980 (1979)) disclose substituted 1,2-dimethyl-5-[4-(phenylthio)]-1H-pyrroles and 1,2-dimethyl-5-[4-(phenylsulfonyl)]-1H-pyrroles that have antileukemic activity.
WO 93/23374 describes the preparation of several indole derivatives that are stated to have antiestrogenic properties.
Dann et al. (Liebigs Ann. Chem. 3: 409-425 (1984)) discloses several indole derivatives having antimicrobial activity.
2-[4-[3-(Aminoiminomethyl)phenoxy]phenyl]-1H-indole-6-carboximidamide has been reported to have antihyperpensive, antitumor, antifertility, antifungal and antibacterial properties.
Compounds of Formula I have not been used heretofor for treating a disorder responsive to the blockade of sodium channels in a mammal.
The present invention is related to the discovery that aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles represented by Formula I are anticonvulsants and act as blockers of sodium (Na+) channels.
The invention is also related with treating a disorder responsive to the blockade of sodium channels in a mammal suffering from excess activity of said channels by administering an effective amount of a compound of Formula I as described herein.
The present invention is also directed to the use of a compound of Formula I for the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions, such as amyotrophic lateral sclerosis (ALS), for the treatment of tinnitus, as antimanic depressants, as local anesthetics, as antiarrhythmics, as anticonvulsants and for the treatment or prevention of diabetic neuropathy and for the treatment of pain including both acute and chronic pain and migraine headache.
Another aspect of the present invention is directed to the use of the compounds of Formula I as blockers of sodium channels.
A third aspect of the present invention is to provide a method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating pain including acute and chronic pain, and neuropathic pain; treating, preventing or ameliorating convulsion and neurodegenerative conditions; treating, preventing or ameliorating manic depression; using as local anesthetics, antiarrhythmics, and treating tinnitus by administering a compound of Formula I to a mammal in need of such treatment.
A further aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the blockade of sodium ion channels, containing an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents.
A number of compounds useful in the present invention have not been heretofor reported. Thus, the present invention is also directed to novel aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles of Formula I.
Further, the present invention is directed to 3H and 14C radiolabeled compounds of Formula I and their use as radioligands for their binding site on the sodium channel.
Additional embodiments and advantages of the invention will be set forth in part of the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The present invention arises out of the discovery that the aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles of Formula I are anticonvulsants and act as blockers of Na+ channels. In view of this discovery, compounds of Formula I are useful for treating disorders responsive to the blockade of sodium ion channels.
The compounds useful in this aspect of the present invention are the aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles represented by Formula I: 
a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
Het is a heteroaryl selected from the group consisting of 
R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, C(O)R14, CH2C(O)R14, S(O)R,4, and SO2R14 all of which may be optionally substituted;
R2, R3, and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, cyano, amino, alkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl, or the R groups in adjacent carbon atoms can be taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle. Examples of bridges formed by R groups taken together are xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94(CH2)3, xe2x80x94(CH2)4xe2x80x94, xe2x80x94OCH2H2Oxe2x80x94, xe2x80x94CH2N(R15)CH2xe2x80x94, xe2x80x94CH2CH2N(R15)CH2xe2x80x94, xe2x80x94CH2N(R15)CH2CHl2xe2x80x94and xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; where R15 is hydrogen, alkyl, or cycloalkyl;
R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; or R9 and R10 or R10 and R11 are taken together with the carbon atoms to which they are attached to form a carbocycle or a heterocycle. Examples of bridges formed by R9 and R10 or R10 and R11 taken together are xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94CH2)3xe2x80x94, xe2x80x94CH2)4xe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94CH2N(R15)CH2xe2x80x94, xe2x80x94CH2CH2N(R15)CH2xe2x80x94, xe2x80x94CH2N(R15)CH2CH2xe2x80x94 and xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; where R15 is defined as above;
R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkynyl, arylalkylamino, dialkylaminoalkenyl, heterocycle, heterocycloalkylamino, and cycloalkylalkylamino, all of which can be optionally substituted; wherein
R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal; and
X is one of O, S, NR15, CH2, NR15C(O), or C(O)NR15, where R15 is defined as above.
One group of useful compounds of the invention are compounds of the general Formula I, wherein Het is (i)-(vi), R1-R16 and X are as defined above with the following provisos that:
1) when Het is (i) or (ii),
a) R1 is H and X is O or S, at least one of R2, R3 and R2-R13 is other than H, except that R11 is not NO2 when R3 is C3, and R3 is not xe2x80x94CH2CH2COOH when the other substituents are each H;
b) R1 is H, X is O and one of R9-R13 is NO2 or OCH3, at least one the other substituents is other than H;
c) X is O, R9 or R13 is CN and a Cl group is ortho to CN, at least one of R2, R3 and R5-R8 is other than H;
d) X is O, R5 and R11 are Cl, at least one of R6, R7, R8, R9, R10, R12 and R13 is other than H;
e) X is O, R2 is methylthio, R1 is H or C(O)R14 wherein R14 is optionally substituted phenyl, at least one of R5-R13 is other than H; or
f) R1 is C(O)NH2 and X is O, at least one of R2, R3 and R5-R13 is other than H;
2) when Het is (iii),
a) R1 is H, X is O or CH2 and R2 and R3 together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, R5-R13 are not all H;
b) R1 is Et and R2 and R3 together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, X is not xe2x80x94NEt; or
c) R1 is H and X is O, R2-R13 are not all H;
3) when Het is (iv) and R1 is H or alkyl, R2-R13 are not all H; or
4) when Het is (vi),
a) X is O, S, or CH2, R2 and R4 do not together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
b) R1 is H and X is O or S, R2-R13 are not all H; or
c) X is S and R1 and R2 both are Me, at least one of R3 and R4 is other thanxe2x80x94CH2OH.
One group of preferred compounds falling within the scope of Formula I include compounds wherein R1 is C(O)R14 or SO2R14, where R14 is amino or C1-6 alkyl and X is O or S.
One group of preferred compounds falling within the scope of Formula I include compounds wherein R1 is optionally substituted heteroaryl, optionally substituted C1-6 alkyl, or CH2C(O)R14, wherein R14 is an optionally substituted heterocycle, such as N-morpholinyl, N-pyrrolidinyl or N-piperazinyl, optionally substituted C1-6 alkyl, C1-6 alkylamino, C1-6 dialkylamino, or OR16, wherein R16 is C1-6 alkyl.
One group of preferred compounds falling within the scope of Formula I include compounds wherein Het is selected from the group consisting of (i), (ii), (iv) and (v).
When Het is (iii), (iv) or (v), R1 is preferably H or alkyl and R2 and R3 are both hydrogen.
Preferably, when Het is (vi), R1 is hydrogen, R2 is selected from the group consisting of aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl, preferably aminocarbonyl, and R3 and R4 are both hydrogen.
One group of preferred compounds falling within the scope of Formula I include compounds wherein Het is selected from the group consisting of (vii), (viii), (ix) and (x).
Preferably, R1 is selected from the group consisting of an alkyl optionally substituted by halogen, hydroxy, carbamoyloxy, C1-6 acyl, C1-6 alkylsulfonylamino, aryl, preferably phenyl, or aminocarbonyl, heteroaryl, preferably pyrimidine, C(O)R14, CH2C(O)R14, or SO2R14, wherein R14 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, OR16, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkenylamino, di(C1-6)alkylaminoalkenyl, heterocycle, and heterocyclo(C1-6)alkyl-amino, all of which can be optionally substituted, and wherein R16 is as defined above.
Preferably, R14 is selected from the group consisting of C1-6 alkyl, C1-6 alkenyl, OR16, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkenylamino, di(C1-6)alkylamino(C2-6)alkenyl, heterocycle, and heterocyclo(C1-6)alkylamino, all of which can be optionally substituted, wherein R16 is as defined above.
Preferably, R2-R4 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino(C1-C6)alkyl, amino, C1-C6 alkylthio, cyano, C1-C6 alkylsulfinyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy, aminocarbonyl, C1-C6 alkylaminocarbonyl, C6-C10 arylaminocarbonyl, C6-C10 aryl(C1-C6)alkylcarbonylamino, C1-C6 alkylcarbonylamino, C6-C10 arylcarbonylamino, C6-C10 aryl(C1-C6)alkylcarbonylamino, C1-C6 alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkylsulfonyl, and heterocyclosulfonyl, more preferably hydrogen, C1-C6 alkyl, C1-C6 alkoxy, amino (C1-C6)alkyl, C1-C6 alkylthio and aminocarbonyl.
Preferred values of R5-R13 include hydrogen, halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2-C6)alkynyl, C1-C6 hydroxyalkyl, nitro, amino, ureido, cyano, C1-C6 acylamido, hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy, or carboxy. The groups R5-R13 each take place of a hydrogen atom that would otherwise be present in any position on the aryl ring to which the R group is attached.
Especially preferred are compounds where R5-R8 are all hydrogen.
Preferably X is O or S, more preferably X is O.
Preferably, R3 and R4 are both H.
Another group of useful compounds of this invention are those having the Formula II: 
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
Het2 is selected from the group consisting of 
A is selected from the group consisting of C(O), CH2C(O), S(O) and SO2;
R2-15 are as defined previously with respect to Formula I; and
X is O or S,
xe2x80x83with the proviso that when Het2 is (i)2 or (ii)2 
a) X is O, R2 is methylthio, R1 is H or C(O)R14 wherein R14 is optionally substituted phenyl, at least one of R5-R13 is other than H; or
b) R1 is C(O)NH2 and X is O, at least one of R2, R3 and R5-R13 is other than H.
Especially preferred compounds with respect to Formula II include those wherein:
R14 is amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylamino or optionally substituted heterocycle, such as N-morpholinyl, N-pyrrolidinyl and N-piperazinyl;
R2, R3, and R4 are independently hydrogen, C1-C6 alkyl, C1-C6 alkylthio or C1-C6 alkylsulfinyl; and
X is O;
xe2x80x83with the proviso that the compound is not 3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide.
Also, preferred compounds of Formula II include those where A is C(O) or CH2C(O), X is O and R14, R2, R3, and R4 are as defined above.
Further, preferred compounds of Formula II include those where A is S(O) or SO2, preferably SO2, R2-R4 are independently H or C1-6 alkyl and X is O. Also, preferred compounds of Formula II include those where A is S(O) or SO2, preferably SO2, R2-R4 are H, R14 is methyl and X is O.
Further another group of useful compounds of the invention are those having the Formula III: 
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
Het3 is selected from the group consisting of 
Rxe2x80x21 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroaryl, C(O)R14, CH2C(O)R14, S(O)R14, and SO2R14;
Rxe2x80x22 is attached to a carbon atom that is not the linking atom attached to the aryl group and is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyano, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl;
Rxe2x80x25, Rxe2x80x26, Rxe2x80x29, and Rxe2x80x210 are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
R14 is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR16, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, cycloalkyl, aralkyl, aryl, heteroaryl, arylalkenyl, arylalkenyl, heterocycle, heterocycloalkyl, and cycloalkylalkylamino, all of which can be optionally substituted; wherein
R16 is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal; and
X is one of O, S, NR15, CH2, NR15C(O), or C(O)NR15 where R15 is defined as above, with the following provisos that:
1) when Het is (i)3 or (ii)3,
a) Rxe2x80x21 is H and X is O or S, at least one of Rxe2x80x22, Rxe2x80x25, Rxe2x80x26, Rxe2x80x29 and Rxe2x80x210 is other than H, except that Rxe2x80x29 or Rxe2x80x210 is not NO2 when Rxe2x80x22 is CH3, and Rxe2x80x22 is not xe2x80x94CH2CH2COOH when the other substituents are each H;
b) Rxe2x80x21 is H, X is O and Rxe2x80x29 or Rxe2x80x210 is NO2 or OCH3, at least one of the other substituents is other than H;
c) X is O, Rxe2x80x29 and Rxe2x80x210 are CN and a Cl group ortho to CN, at least one of Rxe2x80x22, Rxe2x80x25 or Rxe2x80x26 is other than H;
d) X is O, Rxe2x80x25 and Rxe2x80x29 are Cl, at least one of Rxe2x80x26 or Rxe2x80x210 is other than H;
e) X is O, Rxe2x80x22 is methylthio, Rxe2x80x21 is H or C(O)R14 wherein R14 is optionally substituted phenyl, at least one of Rxe2x80x25, Rxe2x80x26, Rxe2x80x29 or Rxe2x80x210 is other than H; or
f) Rxe2x80x21 is C(O)NH2 and X is O, at least one of Rxe2x80x22, Rxe2x80x25, Rxe2x80x26, Rxe2x80x29 or Rxe2x80x210 is other than H;
2) when Het is (iii)3, Rxe2x80x21 is H and X is O, Rxe2x80x25, Rxe2x80x26, Rxe2x80x29 or Rxe2x80x210 are not all H;
3) when Het is (iv)3 and Rxe2x80x21 is H or alkyl, Rxe2x80x25, Rxe2x80x26, Rxe2x80x29 or Rxe2x80x210 are not all H; or
4) when Het is (vi)3, Rxe2x80x21 is H and X is O or S, Rxe2x80x25, Rxe2x80x26, Rxe2x80x29 or Rxe2x80x210 are not all H.
Preferably X is O or S in compounds of Formula III.
Preferably, when Het3 is (i)3 or (ii)3, Rxe2x80x21 is heteroaryl, C(O)R14, CH2C(O)R14, or SO2R14 wherein R14 is amino, alkyl, alkylamino or heterocycle, more preferably amino, all of which can be optionally substituted. When Rxe2x80x22 is aminocarbonyl, Rxe2x80x21 is preferably hydrogen.
Preferably, when Het3 is (vi)3, Rxe2x80x21 is hydrogen and Rxe2x80x22 is selected from the group consisting of aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl, preferably aminocarbonyl.
Preferably, when Het3 is (iii)3, (iv)3 or (v)3, Rxe2x80x21 is hydrogen or alkyl, and Rxe2x80x22 is hydrogen.
Preferably, Rxe2x80x22 is selected from the group consisting of hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, carboxy(C1-C6)alkyl, C1-C6 alkylamino, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, C1-C6 alkylaminosulfonyl, C1-C6 alkylsulfonyl, and heterocyclosulfonyl; more preferably hydrogen, alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, alkoxy(C1-C6)alkyl, alkylthio, alkylamino, and aminocarbonyl. Most preferably Rxe2x80x22 is hydrogen or aminocarbonyl.
Preferably, Rxe2x80x25, Rxe2x80x26, Rxe2x80x29, and Rxe2x80x210 are independently selected from the group consisting of hydrogen, halo, halo(C1-C6)alkyl, C1-C6 alkyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, carboxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, nitro, amino, C1-C6 acylamino, amide, hydroxy, thiol, C1-C6 acyloxy, C1-C6 alkoxy, carboxy, carbonylamido and C1-C6 alkylthiol.
When Het3 is (i)3, (ii)3 or (vi)3, Rxe2x80x22 is preferably attached to a carbon atom adjacent to a nitrogen atom.
Preferably, Het3 is selected from the group consisting of (i)3, (ii)3, (iii)3, (iv)3 and (v)3.
One group of preferable compounds of Formula III include compounds wherein Het3 is (i)3 or (ii)3; Rxe2x80x21 is C(O)R14; Rxe2x80x22 is as defined above; Rxe2x80x25, Rxe2x80x26, and Rxe2x80x210 are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; Rxe2x80x29 is selected from the group consisting of halo, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; and R14-16 and X are as defined above.
Another group of preferable compounds of Formula III include compounds wherein Het3 is (iii)3, (iv)3, (v)3 or (vi)3; Rxe2x80x21 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroaryl. C(O)R14, CH2C(O)R14, S(O)R14, and SO2R14; Rxe2x80x22 is as defined above; Rxe2x80x25, Rxe2x80x26, and Rxe2x80x210 are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; Rxe2x80x29 is selected from the group consisting of halo, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; and R14-16 and X are as defined above.
Further another group of useful compounds of the invention are those having the Formula IV: 
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
Het4 is selected from the group consisting of 
Rxe2x80x22 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyano, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, heterocyclocarbonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, and heterocyclosulfonyl:
Rxe2x80x25, Rxe2x80x26, Rxe2x80x29, and Rxe2x80x210 are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; and
X is one of O, S, NR15, CH2, NR15C(O), or C(O)NR15 where R15 is defined as above.
Het4 is preferably selected from the group consisting of (vii)4 and (x)4. Preferably, Rxe2x80x22, Rxe2x80x25, Rxe2x80x26, Rxe2x80x29, and Rxe2x80x210 are as described for Formula III.
Exemplary preferred compounds that may be employed in this method of invention include, without limitation:
3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole;
5-methylthio-3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide;
5-methylsulfinyl-3-(4-phenoxyphenyl)-1H-pyrazole-1-carboxamide;
3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(4-methoxyphenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(4-aminophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(4-cyanophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(3-chloro-2-cyanophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(4-chloro-2-fluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(2-chloro-4-fluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
1-[3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazolyl]ethanone;
2-methyl-1-[3-(4-phenoxyphenyl)-1H-pyrazole]propanone;
1-methanesulfonyl-3-(4-phenoxy)phenyl-1H-pyrazole;
2-{5-[4-(4-fluorophenoxy)phenyl]-1H-pyrazol-1-yl}-1-(4-methyl)piperazin-1-yl-ethanone;
1-{5-[4-(4-fluorophenoxy)phenyl]-1H-pyrazol-1-yl}-2-methyl-propan-2-ol;
1-{5-[4-(4-fluorophenoxy)phenyl]-1H-pyrazol-1-yl}-propan-2-one;
1-morpholin-4-yl-2-{5-[4-(4-fluorophenoxy)phenyl]-1H-pyrazol-1-yl}-ethanone;
1-[2-(methanesulfonylamino)ethyl]-5-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole;
1-(2-carbamoyloxyethyl)-5-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole;
3-[4-(4-fluorophenylthio)phenyl]-1H-pyrazole-1-carboxamide;
3-[4-(4-fluorophenylthio)phenyl]-1H-pyrazole;
2-[5-[4-(4-fluorophenoxy)phenyl]-pyrazol-1-yl]ethanol;
3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole-1-carboxylic acid dimethylamide;
1-benzyl-5-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole;
2-[3-[4-(4-fluorophenoxy)phenyl]-2H-pyrazol-2-yl]-1-pyrrolidin-1-yl ethanone;
2-(N-methylacetamido)-3-[4-(4-fluorophenoxy)phenyl]-2H-pyrazole;
2-{5-[4-(4-fluorophenoxy)phenyl]-pyrazol-1-yl}-acetamide;
2-{3-[4-(4-fluorophenoxy)phenyl]-pyrazol-1-yl}-acetamide;
3-{5-[4-(4-fluorophenoxy)phenyl]-pyrazol-1-yl}-propionamide;
3-[3-fluoro-4-(4-fluorophenoxy)phenyl]-1H-pyrazole-1-carboxamide;
2-{3-[4-(4-fluorophenoxy)phenyl]-pyrazol-1-yl}-pyrimidine; and
2-{3-[4-(4-trifluoromethylphenoxy)phenyl-1-pyrazol-1-yl}pyrimidine.
Additional useful compounds of the present invention include:
4-[4-(4-fluorophenoxy)phenyl]-1H-imidazole;
4-[4-(4-fluorophenoxy)-3-fluorophenyl]-1H-imidazole;
4-[4-(4-fluorophenoxy)-3-fluorophenyl]-1H-imidazole, hydrochloride salt;
4-[4-(2,4-difluorophenoxy)phenyl]-1H-imidazole;
4-[4-(2,4-difluorophenoxy)phenyl]-1H-imidazole, hydrochloride salt;
4-[4-(2-fluoro-4-chlorophenoxy)phenyl]-1-imidazole, hydrochloride salt;
4-(4-(4-trifluoromethylphenoxy)phenyl]-1H-imidazole, hydrochloride salt;
4-[4-(2,4-difluorophenoxy)phenyl]-2-methyl-1H-imidazole;
4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole-2-carboxamide;
2-[4-(4-fluorophenoxy)phenyl]-1H-imidazole, hydrochloride salt;
2-[4-(4-fluorophenoxy)phenyl]-1H-benzimidazole;
2-[4-(4-fluorophenoxy)phenyl]-1H-imidazole-4-carboxamide;
2-[4-(4-fluorophenoxy)phenyl]-1H-imidazole-4-carbonitrile;
5-[4-(4-fluorophenoxy)phenyl]-pyrrole-2-carboxamide;
5-(4-phenoxyphenyl)pyrrole-2-carboxamide;
methyl 5-[4-(4-fluorophenoxy)phenyl]pyrrole-2-carboxylate;
2-[4-(4-fluorophenoxy)phenyl]oxazole-4-carboxamide; and
4-[4-(4-fluorophenoxy)-3-fluorophenyl]thiazole-2-carboxamide.
Useful aryl groups are C6-14 aryl, especially C6-10 aryl. Typical C6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
Useful cycloalkyl groups are C3-8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term xe2x80x9cheteroarylxe2x80x9d as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 xcfx80 electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazonyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl groups).
Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
Useful alkyl groups include straight-chained and branched C1-10 alkyl groups, more preferably C1-6 alkyl groups. Typical C1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylene group substituted on two adjoining positions on the benzene ring of the compounds of the invention.
Useful alkenyl groups are C2-6 alkenyl groups, preferably C2-4 alkenyl. Typical C2-4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.
Useful alkynyl groups are C2-6 alkynyl groups, preferably C2-4 alkynyl. Typical C2-4 alkynyl groups include ethenyl, propynyl, butynyl, and 2-butynyl groups.
Useful arylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned C6-14 aryl groups. Useful values include benzyl, phenethyl and naphthylmethyl.
Useful arylalkenyl groups include any of the above-mentioned C2-4 alkenyl groups substituted by any of the above-mentioned C6-14 aryl groups.
Useful arylalkynyl groups include any of the above-mentioned C2-4 alkynyl groups substituted by any of the above-mentioned C6-14 aryl groups. Useful values include phenylethynyl and phenylpropynyl.
Useful heteroarylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heteroaryl groups.
Useful heteroarylalkenyl groups include any of the above-mentioned C2-4 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
Useful heteroarylalkynyl groups include any of the above-mentioned C2-4 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.
Useful cycloalkylalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned cycloalkyl groups.
Useful haloalkyl groups include C1-10 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.
Useful hydroxyalkyl groups include C1-10 alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.
Useful alkoxy groups include oxygen substituted by one of the C1-10 alkyl groups mentioned above.
Useful alkylthio groups include sulfur substituted by one of the C1-10 alkyl groups mentioned above.
Useful acylamino groups are any C1-6 acyl (alkanoyl) attached to an amino nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted C2-6 substituted acyl groups.
Useful acyloxy groups are any C1-6 acyl (alkanoyl) attached to an oxy (xe2x80x94Oxe2x80x94) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
The term heterocycle is used herein to mean saturated or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples include, but are not limited to, pyrrolidine, piperazine, morpholine, imidazoline, pyrazolidine, benzodiazepines and the like.
Useful heterocycloalkyl groups include any of the above-mentioned C1-10 alkyl groups substituted by any of the above-mentioned heterocyclic groups.
Useful alkylamino and dialkylainino groups are xe2x80x94NHR17 and xe2x80x94NR17R18, wherein R17 and R18 are C1-10 alkyl groups.
Aminocarbonyl group is xe2x80x94C(O)NH2.
Useful alkylaminocarbonyl groups are carbonyl groups substituted by xe2x80x94NHR17 and xe2x80x94NR17R18, wherein R17 and R18 are C1-10 alkyl groups as defined above.
Useful alkylcarbonyl groups are carbonyl groups substituted by any of the above-mentioned C1-10 alkyl groups.
Useful alkylthiol groups include any of the above-mentioned C1-10 alkyl groups substituted by a xe2x80x94SH group.
Useful alkylsulfinyl groups include any of the above-mentioned C1-10 alkyl groups attached to a sulfinyl (xe2x80x94SOxe2x80x94).
Useful alkylsulfonyl groups include any of the above-mentioned C1-10 alkyl groups attached to a sulfonyl (xe2x80x94SO2xe2x80x94).
Useful alkylaminosulfonyl groups include xe2x80x94NHR17 and xe2x80x94NR17R18 groups attached to a sulfonyl, wherein R17 and R18 are C1-10 alkyl groups as defined above.
Aminosulfonyl is xe2x80x94SO2NH2 ,
A carbamoyloxy group is xe2x80x94Oxe2x80x94C(O)xe2x80x94NH2.
A carboxy group is xe2x80x94COOH.
An azido group is xe2x80x94N3.
An ureido group is xe2x80x94NHxe2x80x94C(O)xe2x80x94NH2.
An amino group is xe2x80x94NH2.
An amide group is an organic radical having xe2x80x94NHC(O)xe2x80x94 as a functional group.
Optional substituents on R1, Rxe2x80x21 and R14-R16 include any one of halo, halo(C1-6)alkyl, aryl, heterocycle, cycloalkyl, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, cycloalkyl(C1-6)alkyl, heterocyclo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, carboxy(C1-6)alkyl, alkoxy(C1-6)alkyl, nitro, amino, ureido, cyano, C1-6 acylamino, hydroxy, thiol, C1-6 acyloxy, azido, C1-6 alkoxy, carboxy, aminocarbonyl, carbamoyloxy, C1-6 alkylsulfonylamino, C1-6 acyl, and C1-6 alkylthiol groups mentioned above. Preferred optional substituents include: halo, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, hydroxy, nitro, C1-6 alkyl, C1-6 alkoxy, aminocarbonyl, carbamoyloxy, C1-6 alkylsulfonylamino, C1-6 acyl and amino.
Unlike the semicarbazones disclosed by Dimmock et al. in U.S. Pat. No. 5,741,818, which are somewhat flexible molecules, the pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles are much more rigid. In addition, the electronics of the pyrazole, imidazole, oxazole, thiazole and pyrrole ring are very different from that of a semicarbazone. For example, the 2xe2x80x2-nitrogen present in the semicarbazone is now replaced with the nitrogen atom at the 2-position of the pyrazole and thus is part of the six electron aromatic ring. Unlike the aminoalkanamides described by Pevarello, which contain a basic amine (pKa greater than 7), the heteroaryl compounds of the invention do not have to be basic. Pyrazole, for example, is half-protonated only at pH 2.5 and substitution with an electron withdrawing carbonyl is expected to reduce its basicity further. In addition, it was found that the primary amides present in the semicarbazones and the aminopropionamides are not necessary for activity as sodium channel blockers in the aryl-pyrazoles and -imidazoles claimed in the present application. Based on these considerations, it is an unexpected finding that the aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles show good activity as sodium channel blockers.
Since the compounds of Formula I are blockers of sodium (Na+) channels, a number of diseases and conditions mediated by sodium ion influx can be treated employing these compounds. Therefore, the invention is related to a method of treating, preventing or ameliorating neuronal loss associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, spinal cord trauma: as well as treating or ameliorating neurodegenerative diseases including Alzheimer""s disease, amyotrophic lateral sclerosis, Parkinson""s disease, treating or ameliorating anxiety, convulsions, glaucoma, migraine headache, and muscle spasm. The compounds of Formula I are also useful as antitinnitus agents, antimanic depressants, as local anesthetics, and as antiarrhythmics; as well as for treating, preventing or ameliorating pain including surgical, chronic and neuropathic pain. In each instance, the methods of the present invention require administering to an animal in need of such treatment an effective amount of a sodium channel blocker of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.
The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed compounds. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, secium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like.
The invention disclosed herein is also meant to encompass prodrugs of the disclosed compounds. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug in vivo.
The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled compound of the invention, administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur and isolating its conversion products from the urine, blood or other biological samples.
The invention disclosed herein is also meant to encompass the disclosed compounds being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.
Some of the compounds disclosed herein may contain one or more asymmetric centers and my thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.
As used herein, the term xe2x80x9cstereoisomersxe2x80x9d is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached.
The term xe2x80x9cenantiomerxe2x80x9d or xe2x80x9cenantiomericxe2x80x9d refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
The term xe2x80x9cracemicxe2x80x9d refers to a mixture of equal parts of enantiomers and which is optically inactive.
The term xe2x80x9cresolutionxe2x80x9d refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
The invention is also directed to a method for treating disorders responsive to the blockade of sodium channels in animals suffering thereof. Particular preferred embodiments of the aryl substituted heteroaryl compounds for use in method of this invention are represented by previously defined Formulae I-IV.
The compounds of this invention may be prepared using methods known to those skilled in the art. The 1H-pyrazoles of the present invention can be prepared as illustrated by exemplary reactions in Scheme 1 and 2. Scheme 1 illustrates the formation of a pyrazole-1-carboxamide from the corresponding 3-substituted-1H-pyrazole using sodium cyanate: 
The 3-substituted-1H-pyrazoles were prepared as shown in Scheme 2 or were commerically available. 3-(4-Phenoxyphenyl)-1H-pyrazole, 3-[(4-nitrophenoxy)phenyl]-1H-pyrazole, 3-[(4-methoxyphenoxy)phenyl]-1H-1-pyrazole, 5-methylthio-3-(4-phenoxyphenyl)-1H-pyrazole and 3-[(3-chloro-2-cyanophenoxy)phenyl]-1H-pyrazole were obtained from Ryan Scientific (Isle of Palms, S.C.). 
The 1,5-disubstituted pyrazoles can be prepared as shown in Scheme 3. 
Compounds with Formula I wherein Het is (iii) can be prepared as illustrated by exemplary reactions in Scheme 4. 
Compounds with Formula I where Het is (iv) and (v) can be prepared as illustrated by exemplary reactions in Scheme 5. 
Compounds with Formula I where Het is (vi) can be prepared as illustrated by exemplary reactions in Scheme 6 using the method of Pichon, M. et al (Tetrahedron Lett. 37: 7963-7966 (1966)) and Fournie-Zaluski, M-C. et al. (J. Med. Chem. 39: 2594-2608 (1996)). 
Compounds with Formula I wherein Het is (vii) can be prepared as illustrated in exemplary reactions in Sceme 7. 
Compounds with Formula I where Het is (x) can be prepared as illustrated by examplary reactions in Scheme 8. 
The invention is also directed to 3H and 14C radiolabeled compounds of Formula I and their use as radioligands for their binding site on the sodium channel. For example, one use of the labeled compounds of the invention is the characterization of specific receptor binding. Another use of the labeled compounds of the invention is an alternative to animal testing for the evaluation of structure-activity relationships. The receptor assay is performed at a fixed concentration of a labeled compound of Formula I and at increasing concentrations of a test compound in a competition assay.
Tritiated compounds of Formula I can be prepared by introducing tritium into the compound of Formula I by, for example, catalytic dehalogenation with tritium. This method includes reacting a suitably halogen-substituted precursor of a compound of Formula I with tritium gas in the presence of a suitable catalyst, for example Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritiated compounds can be found in Filer, Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6. 14C-labeled compounds can be prepared by employing starting materials having a 14C carbon.
The compounds of the present invention were assessed by electrophysiological assays in dissociated hippocampal neurons for sodium channel blocker activity. These compounds also could be assayed for binding to the neuronal voltage-dependent sodium channel using rat forebrain membranes and [3H]BTX-B.
Sodium channels are large transmembrane proteins that are expressed in various tissues. They are voltage sensitive channels and are responsible for the rapid increase of Na+ permeability in response to depolarization associated with the action potential in many excitable cells including muscle, nerve and cardiac cells.
One aspect of the present invention is the discovery of the mechanism of action of the compounds herein described as specific Na+ channel blockers. Based upon the discovery of this mechanism, these compounds are contemplated to be useful in treating or preventing neuronal loss due to focal or global ischemia, and in treating or preventing neurodegenerative disorders including ALS, anxiety, and epilepsy. They are also expected to be effective in treating, preventing or ameliorating neuropathic pain, surgical pain, chronic pain and tinnitus. The compounds are also expected to be useful as antiarrhythmics, anesthetics and antimanic depressants.
The present invention is directed to compounds of Formulae I-IV that are blockers of voltage-sensitive sodium channels. According to the present invention, those compounds having preferred sodium channel blocking properties exhibit an IC50 of about 100 xcexcM or less in the electrophysiological assay described herein. Preferably, the compounds of the present invention exhibit an IC50 of 10 xcexcM or less. Most preferably, the compounds of the present invention exhibit an IC50 of about 1.0 xcexcM or less. Substituted heteroaryl compounds of the present invention may be tested for their Na+ channel blocking activity by the following electrophysiological and binding assays.
Cell preparation: HEK-293 cells stably expressing the hSkM1 isoform of Na+ channels (generous gift from Dr. A. L. George, Vanderbilt University Medical School) were cultured using standard techniques, as described previously (Verdoorn, T. A, et al., Neuron 4:919-928 (1990)). For electrophysiology, cells were plated onto 35 mm Petri dishes (pre-coated with poly-D-lysine) at a density of 1:40 on the day of re-seeding from confluent cultures. Our experience has been that cells are suitable for recordings for 2-3 days after plating.
Patch-clamp recordings of voltage-sensitive Na+ currents: Whole-cell voltage-clamp recordings were made using conventional patch-clamp techniques (Hamill et al., Pfluegers Arch. 391:85-100 (1981)) with an Axopatch 200A amplifier (Axon Instruments, Foster City, Calif.). Recordings were made within 2-3 hours after neuron dissociation. The recording chamber was continuously superfused with the external solution (150 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH 7.4 (NaOH)) at a speed of about 1 mL/min. Recording pipettes were pulled from thick-walled capillaries (WPI, Sarasota, Fla.) and fire-polished. The pipette resistances ranged from 1 to 3 Mxcexa9 when the pipettes were filled with internal solution containing (in mM): 110 CsF, 10 NaCl, 5 MgCl2, 11 EGTA, 10 HEPES, pH adjusted to 7.4 with CsOH. Osmolality was set with a difference of 15-20 mmol/kg between external and internal solutions (lower inside the cell). Drugs and intervening wash-outs were applied through a linear array of flow pipes (Drummond Microcaps, 2 xcexcL, 64-mm length). Compounds are dissolved in dimethylsulfoxide (DMSO) to make a 30 mM stock solution, which was subsequently diluted into the external solution to give final concentrations of 0.1-100 xcexcM. At the highest (1%) concentration, DMSO inhibited the size of Na+ current only slightly. Currents were recorded at room temperature (22-25xc2x0 C.), filtered at 5 kHz with an active 8-pole Bessel filter (Frequency Devices, Haverhill, Mass.), digitized at 10-50 xcexcs intervals, and stored using Digidata 1200 analog/digital interface with Pclamp6/Clampex software (Axon Instruments). Series resistance was cancelled typically by xcx9c75% when necessary. The inhibitory potency of drugs was assessed by measuring reductions in the peak amplitude of Na+ currents induced by increasing concentrations of compounds tested. Na+ currents were elicited by stepping membrane voltage from holding potentials over the range xe2x88x92100 mV to xe2x88x9250 mV, to a pulse potential of xe2x88x9210 mV. The test pulse duration was 5-10 msec, repeated at a frequencyxe2x89xa61 Hz. Concentration-inhibition curves were fitted with equation 1:
I/Icontrol=1/(1+([compound]/IC50))xe2x80x83xe2x80x83Eq. 1
where Icontrol is the maximal Na+ current in the absence of antagonist, [compound] is the drug concentration, and IC50 is the concentration of compound that produces half maximal inhibition.
Cell preparation: HEK-293 (NaIIA-B2) cell line stably expressing the rBIIA isoform of Na+ channels was established in-house. The cells were cultured using standard techniques, as described previously (Verdoorn, T. A, et al., Neuron 4:919-928 (1990)). For electrophysiology, cells were plated onto poly-D-lysine pre-coated Cellware 35 mm Petri dishes (BIOCOAT, Becton Dickinson) at a density of xcx9c104 cells/dish on the day of re-seeding from confluent cultures. Our experience has been that cells are suitable for recordings for 2-3 days after plating.
Patch-clamp recordings of voltage-sensitive Na+ currents. Whole-cell voltage-clamp recordings were made using conventional patch-clamp techniques (Hamill et al., Pfluegers Arch. 391:85-100 (1981)) with an Axopatch 200A amplifier (Axon Instruments, Foster City, Calif.). The recording chamber was continuously superfused with the external solution (150 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH7.4 adjusted with NaOH, osmolality xcx9c320 mmol/kg) at a speed of about 1 mL/min. Recording pipettes were pulled from the thick-walled capillaries (WPI, Sarasota, Fla.) and fire-polished. The pipette resistances ranged from 1 to 3 Mxcexa9 when the pipettes were filled with internal solution containing (in mM): 130 CsF, 20 NaCl, 2 MgCl2, 10 EGTA, 10 HEPES, pH adjusted to 7.4 with CsOH, osmolality xcx9c310 mmol/kg. Drugs and intervening wash-outs were applied through a linear array of flow pipes (Drummond Microcaps, 2 xcexcL, 64-mm length). Compounds are dissolved in dimethylsulfoxide (DMSO) to make a 30 mM stock solution, which was subsequently diluted into the external solution to give final concentrations of 0.1-100 xcexcM. At the highest (1%) concentration, DMSO inhibited the size of Na+ current only slightly. Currents were recorded at room temperature (22-25xc2x0 C.), filtered at 3 kHz with an active 8-pole Bessel filter (Frequency Devices, Haverhill, Mass.), digitized at 10-50 xcexcs intervals, and stored using Digidata 1200 analog/digital interface with Pclamp6/Clampex software (Axon Instruments). Series resistance was cancelled typically by xcx9c75% when necessary.
The following voltage pulse protocols were used to assess the potency and kinetics of inhibition of the Na+ channels by the compounds (FIG. 1). 
FIG. 1. Voltage pulse protocols. A. IV-curves. C. Steady-state inactivation. B. Repriming kinetics. D. Time course of binding.
Current-voltage relationship (IV-curve), protocol A, was used to report the voltage at which the maximal inward Na+ current is achieved. This voltage was used throughout the experiment as testing voltage, Vt. The steady-state inactivation (or, availability) curve, protocol C, was used to get the voltage at which almost complete (xe2x89xa795%) inactivation of Na+ channels occurs; it served as voltage for conditioning prepulse, Vc, throughout the experiment. Protocol B reports how fast the channels recover from inactivation at hyperpolarized voltages. This permitted us to set up the duration of the hyperpolarization gap which is used in measurement of the kinetics of binding of compounds to inactivated Na+ channels (protocol D). Channel repriming under control conditions was fast (xe2x89xa790% recovery during first 5-10 ms). If a drug substantially retards the repriming process then it becomes possible (protocol D) to accurately measure the kinetics of binding of the inhibitor to inactivated channels as well as the steady-state affinity (k+ and Ki). To estimate k+ values the reduction in peak currents in successive trials with varying pre-pulse duration was plotted as a function of pre-pulse duration and the time constant (xcfx84) measured by mono-exponential fit. A plot of 1/xcfx84 as a function of antagonist concentration then allowed calculating of the macroscopic binding rates of the antagonists. To determine Ki values the partial inhibition curves measured by fractional responses in steady-state were fitted with the logistic equation:
xe2x80x83I/Icontrol=1/(1+([antagonist]/Ki)p),xe2x80x83xe2x80x83Eq. 2
where Icontrol is the maximal Na+ current in the absence of antagonist, [antagonist] is the drug concentration, Ki is the concentration of antagonist that produces half maximal inhibition, and p is the slope factor.
The ability of compounds of the present invention to modulate either site 1 or site 2 of the Na+ channel was determined following the procedures fully described in Yasushi, J. Biol. Chein. 261:6149-6152 (1986) and Creveling, Mol. Pharmacol. 23:350-358 (1983), respectively. Rat forebrain membranes were used as sources of Na+ channel proteins. The binding assays were conducted in 130 xcexcM choline chloride at 37xc2x0 C. for 60-minute incubation with [3H] saxitoxin and [3H] batrachotoxin as radioligands for site 1 and site 2, respectively.
The compounds of the present invention may be tested for in vivo anticonvulsant activity after i.v., p.o. or i.p. injection using a number of anticonvulsant tests in mice, including the maximum electroshock seizure test (MES). Maximum electroshock seizures were induced in male NSA mice weighing between 15-20 g and male Sprague-Dawley rats weighing between 200-225 g by application of current (50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C., mice; 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C., rats) using a Ugo Basile ECT device (Model 7801). Mice were restrained by gripping the loose skin on their dorsal surface and saline-coated corneal electrodes were held lightly against the two corneae. Rats were allowed free movement on the bench top and ear-clip electrodes were used. Current was applied and animals were observed for a period of up to 30 seconds for the occurrence of a tonic hindlimb extensor response. A tonic seizure was defined as a hindlimb extension in excess of 90 degrees from the plane of the body. Results were treated in a quantal manner.
The compounds may be tested for their antiociceptive activity in the formalin model as described in Hunskaar, S., O. B. Fasmer, and K. Hole, J. Neurosci. Methods14: 69-76 (1985). Male Swiss Webster NIH mice (20-30 g; Harlan, San Diego, Calif.) were used in all experiments. Food was withdrawn on the day of experiment. Mice were placed in Plexiglass jars for at least 1 hour to accommodate to the environment. Following the accommodation period mice were weighed and given either the compound of interest administered i.p. or p.o., or the appropriate volume of vehicle (10% Tween-80). Fifteen minutes after the i.p. dosing, and 30 minutes after the p.o. dosing mice were injected with formalin (20 xcexcL of 5% formaldehyde solution in saline) into the dorsal surface of the right hind paw. Mice were transferred to the Plexiglass jars and monitored for the amount of time spent licking or biting the injected paw. Periods of licking and biting were recorded in 5 minute intervals for 1 hour after the formalin injection. All experiments were done in a blinded manner during the light cycle. The early phase of the formalin response was measured as licking/biting between 0-5 min, and the late phase was measured from 15-50 min. Differences between vehicle and drug treated groups were analyzed by one-way analysis of variance (ANOVA). A P valuexe2x89xa60.05 was considered significant. Having activity in blocking the acute and second phase of formalin-induced paw-licking activity, the compounds are considered to be efficacious for acute and chronic pain. The compounds may be tested for their potential for the treatment of chronic pain (antiallodynic and antihyperalgesic activities) in the Chung model of peripheral neuropathy. Male Sprague-Dawley rats weighing between 200-225 g were anesthetized with halothane (1-3% in a mixture of 70% air and 30% oxygen) and their body temperature controlled during anesthesia through use of a homeothermic blanket. A 2-cm dorsal midline incision was then made at the L5 and L6 level and the para-vertibral muscle groups retracted bilaterally. L5 and L6 spinal nerves were then be exposed, isolated, and tightly ligated with 6-0 silk suture. A sham operation was performed exposing the contralateral L5 and L6 spinal nerves as a negative control.
Tactile Allodynia: Rats were transferred to an elevated testing cage with a wire mesh floor and allowed to acclimate for five to ten minutes. A series of Semmes-Weinstein monofilaments were applied to the plantar surface of the hindpaw to determine the animal""s withdrawal threshold. The first filament used possessed a buckling weight of 9.1 gms (0.96 log value) and was applied up to five times to see if it elicited a withdrawal response. If the animal had a withdrawal response then the next lightest filament in the series would be applied up to five times to determine if it could elicit a response. This procedure was repeated with subsequent lesser filaments until there was no response and the lightest filament that elicited a response was recorded. If the animal did not have a withdrawal response from the initial 9.1 gms filament then subsequent filaments of increased weight were applied until a filament elicited a response and this filament was then recorded. For each animal, three measurements were made at every time point to produce an average withdrawal threshold determination. Tests were performed prior to and at 1, 2, 4 and 24 hours post drug administration. Tactile allodynia and mechanical hyperalgesia tests were conducted concurrently.
Mechanical Hyperalgesia: Rats were transferred to an elevated testing cage with a wire mesh floor and allowed to acclimate for five to ten minutes. A slightly blunted needle was touched to the plantar surface of the hindpaw causing a dimpling of the skin without penetrating the skin. Administration of the needle to control paws typically produced a quick flinching reaction, too short to be timed with a stopwatch and arbitrarily given a withdrawal time of 0.5 sec. The operated side paw of neuropathic animals exhibited an exaggerated withdrawal response to the blunted needle. A maximum withdrawal time of ten seconds was used as a cutoff time. Withdrawal times for both paws of the animals were measured three times at each time point with a five-minute recovery period between applications. The three measures were used to generate an average withdrawal time for each time point. Tactile allodynia and mechanical hyperalgesia tests were conducted concurrently.
The compounds may be tested for their neuroprotective activity after focal and global ischemia produced in rats or gerbils according to the procedures described in Buchan et al. (Stroke, Suppl. 148-152 (1993)) and Sheardown et al. (Eur. J. Pharmacol. 236:347-353 (1993)) and Graham et al. (J. Pharmacol. Exp. Therap. 276:1-4 (1996)).
The compounds may be tested for their neuroprotective activity after traumatic spinal cord injury according to the procedures described in Wrathall et. al. (Exp. Neurology 137:119-126 (1996)) and Iwasaki et. al. (J. Neuro Sci. 134:21-25 (1995)).
Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for epilepsy, neurodegenerative diseases, anesthetic, arrhythmia, manic depression, and pain. For intramuscular injection, the dose is generally about one-half of the oral dose.
In the method of treatment or prevention of neuronal loss in global and focal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia, status epilepsy and surgery, the compound can be administrated by intravenous injection at a dose of about 0.025 to about 10 mg/kg.
The unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. Preferably, the preparations, particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the particular heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like. Basic salts are formed by mixing a solution of the heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
The pharmaceutical compositions of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxy-propylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
Possible pharmaceutical preparations, which can be used rectally, include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, and include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.